Our aim is to characterize the molecular interactions of a large protein superfamily of >180 related antigens (termed SRS for SAG1-Related Sequences) the protozoan parasite T. gondii employs to modulate immunity and attach to and invade virtually any nucleated cell. The SRS superfamily is not apparently engaged in antigenic variation in the strict sense because multiple sets of SRS proteins are simultaneously expressed. The SRS proteins are regulated in a developmental-specific rather than individual-specific manner as seen, for example, with African trypanosomes. Investigations of the SRS adhesin proteins expressed on the parasite surface will help us to understand how the Toxoplasma parasite attaches to host cells and escapes elimination by the immune system. We hypothesize that collectively, the SRS antigens function as a set of quasi-redundant receptors for entry into the broad spectrum of cell types and hosts Toxoplasma infects. However, a subset of the SRS proteins appear to have a greater role in subversion of host immunity. In ongoing studies this year, we have demonstrated that three of the SRS proteins, SAG1, SRS2 and SAG3, appear to be critical virulence determinants required for successful infection. SAG3 is a pivotal adhesin required for establishing infection, whereas the adhesins SAG1 and SRS2 are immunomodulating factors that elicit strong immunity in all infected hosts. Our work with SRS2 identified that the majority of virulent Toxoplasma strains using a mouse model of infection poorly express SRS2, whereas all avirulent strains are high expressors of SRS2. We tested whether the expression level of SRS2 was sufficient to alter the mouse virulence phenotype. When SRS2 was expressed transgenically in a mouse virulent strain at levels equivalent to those found in avirulent strains, the transgenic strains were no longer virulent. These data suggest that the SRS2 molecule is a pivotal virulence factor and that expression level was critical to the outcome of these pathogenesis studies. Because SRS2 is expressed only on the fast-growing tachyzoite stage, we believe SRS2 exists to activate innate immune pathways in order to regulate the virulence of the tachyzoite stage. Understanding the molecular basis of host cell entry within this superfamily of SRS antigens, and the type of immunity induced during natural infections should lay the foundation for therapeutic interventions, either prophylactic or vaccine-based, to limit infectivity and induce sterilizing immunity against this widespread zoonotic pathogen. Eliminating the ability of this parasite to establish persistent, life-long infections in humans and animals is central to controlling its pathogenesis, since there is currently no human vaccine or drug capable of doing this.